The ultimate aim of this project is to use a genetic approach to better understand the molecular basis of human bipolar affective disease (BAD). Our goal is to develop an efficient strategy for isolating and characterizing BAD genes that have been identified through linkage analysis. Specifically, this project will concentrate on the autosomal dominant gene deficit found in bipolar affective disease (BAD) in a large Old Order Amish family pedigree. In this pedigree, the genetic defect has recently been located by restriction fragment length polymorphism mapping to chromosome 11. The general strategy of this project involves identifying DNA probes that physically flank the BAD disease gene, cloning all the DNA between the flanking probes, and identifying the BAD disease gene in the cloned DNA. This project emphasizes both genetic and physical mapping approaches to isolate the defective gene. We will generate single-copy, unique human sequence DNA probes in the vicinity of the BAD gene, and then establish the order of these probes with respect to each other and other known chromosome 11 markers by a somatic cell genetic technique developed in this lab known as "radiation hybrid mapping". We will use a subset of these ordered DNA probes in conjunction with genomic DNA samples from individuals in the Amish BAD pedigree to define probes that flank the BAD gene. We will then clone 500-1000 kb segments of human chromosome 11 in yeast artificial chromosomes (YACs) containing all the intervening DNA specified by the flanking BAD probes. Finally we will use several approaches to identify candidate genes for BAD residing in YAC DNA sequences deliniated by the two flanking markers. Elucidation of the BAD gene defect will provide for presymptomatic testing of individuals at risk for the disease, and offer new therapeutic approaches based on the protein abnormality coded by the disease gene.